December 08, 2008 -- ANN ARBOR, Mich.---Scientists have identified 12 new genes that are
somewhat strange bedfellows: Some link gallstones and blood cholesterol
levels, others link melatonin and sleep patterns to small increases in
glucose levels and larger jumps in the risk of diabetes.

While
these associations are surprising, all the genes are potential new drug
targets and some of them could help explain conditions that have been a
mystery. Nature Genetics will publish two papers explaining the
findings online Dec 7, in advance of the January print edition.

The 12 new genes relate to cholesterol and glucose
levels, but several point to somewhat surprising links between these
traits and other conditions, said Goncalo Abecasis, associate professor
of biostatistics at the University of Michigan School of Public Health
who co-directed the cholesterol study. Cristen Willer, a postdoctoral
researcher working with Michael Boehnke, a professor at the U-M SPH,
was lead analyst and joint first author of the study along with Sekar
Kathiresan of Massachusetts General Hospital and Harvard Medical School.

Cholesterol
is a strong predictor of heart disease and in a previous study,
Abecasis, Boehnke, Willer and colleagues had shown that genetic
variants that raise LDL cholesterol (low density lipoprotein or
so-called bad cholesterol) levels also increase the risk of heart
disease. The current study describes the most detailed assessment of
the genetics of cholesterol to date, examining genetic variants and
cholesterol levels in more than 40,000 individuals.

"An
important finding is that several of these genes have multiple
different changes that can affect cholesterol," Willer said. For
example, in the PCSK9 gene there are common variants that affect about
40 percent of the population and increase LDL by about 3-6 milligrams
per deciliter, a fairly small amount. Another variant affects roughly 2
percent of individuals but increases LDL by about 15-30 milligrams per
deciliter. Finally, there are extremely rare changes in the same gene
that affect fewer than 1 in 1000 people but can increase LDL by well
over 100 milligrams per deciliter.

"We think looking at this
list of genes in individuals with extremely high cholesterol may
clarify a lot of those unexplained cases," Abecasis said.

In the
cholesterol study, U-M scientists and collaborators at more than 10
institutions in the U.S. and Europe located 30 genetic variants
associated with cholesterol levels, including 11 new ones. Notably,
several of the newly implicated genetic variants were also related to
the risk of gallstones and certain rare forms of diabetes.

"Each
of these genes is a potentially interesting drug target," said
Abecasis. Statins, a class of cholesterol lowering drugs used to reduce
the risk of heart disease, target the HMGCR gene, one of the genes
identified in the study. The other genes identified in the study could
lead to entirely new and more effective therapies to manage cholesterol
levels and reduce the risk of heart disease. In addition, the genetic
changes they identify can also help predict whether each individual
will develop high LDL or low HDL.

In the paper studying glucose
levels, Abecasis and Boehnke collaborated with researchers across the
globe to discover genetic changes strongly associated with a small
increase in glucose levels in non-diabetic individuals. They also found
the same changes increased the risk of developing diabetes by up to 20
percent.

"Observing an increased risk for diabetes was
surprising because the changes in glucose levels were well within the
normal range," said Boehnke, who has studied the genetics of diabetes
for more than 15 years.

The gene, called the melatonin receptor,
helps regulate the circadian clock, among other things. The finding
strengthens the association between disrupted sleep patterns and
diabetes, Boehnke said.

In the glucose study, scientists looked at the genomes of 36,000 individuals.